RESUMEN
Peptides derived from pro-opiomelanocortin, including alpha-MSH and ACTH, play important roles in the regulation of feeding. We investigated the central effect of ACTH 1-39 (ACTH) and peptides derived from the N-terminus (ACTH 1-10, Acetyl-ACTH 1-13-amide [alpha-MSH]) and C-terminus (ACTH 18-39 and ACTH 22-39) of this peptide on feeding in 16 hour-fasted or rats fed ad libitum. As expected, ACTH reduced feeding in fed and previously fasted rats, although this anorectic effect was more pronounced in fasted rats. The N-terminal-derived peptide alpha-MSH, but not ACTH 1-10, reduced cumulative food intake over 2 h after its injection intracerebroventricularly (icv) in 16 h-fasted, but not in fed rats. In contrast, the C-terminal fragments produced a long-lasting increase in feeding in fasted, but not in fed rats. The anorectic effects of N-terminal fragments of ACTH are recognised to be mediated via melanocortin MC4 receptors. However, the orexigenic effects of the C-terminal fragments do not appear to be conducted via MC4 receptors, since neither ACTH 18-39 nor ACTH 22-39 stimulated cAMP accumulation nor inhibited the ACTH-stimulated cAMP accumulation in HEK-293 cells transfected with the recombinant MC4 receptor.
Asunto(s)
Hormona Adrenocorticotrópica/farmacología , Ingestión de Alimentos/efectos de los fármacos , Fragmentos de Péptidos/farmacología , Receptores de Corticotropina/efectos de los fármacos , Animales , Línea Celular , AMP Cíclico/agonistas , AMP Cíclico/análisis , Ingestión de Alimentos/fisiología , Ayuno , Humanos , Masculino , Ratas , Ratas Sprague-Dawley , Receptor de Melanocortina Tipo 4 , Receptores de Corticotropina/metabolismo , Proteínas Recombinantes/efectos de los fármacosRESUMEN
The effects of centrally injected orexin-A on plasma adrenocorticotropin (ACTH) and corticosterone levels and corticotropin releasing factor (CRF) and arginine vasopressin (AVP) mRNA in the parvocellular cells of the paraventricular nucleus (PVN) of the rat were investigated. In animals implanted previously with a lateral brain ventricle and femoral artery cannula, a single i.c.v. injection of orexin-A (10 microg/rat) resulted in a rapid, significant increase in plasma ACTH and corticosterone concentrations. Plasma ACTH reached a peak (12.5-fold greater than basal levels) at 30 min, which was maintained over 120 min before declining towards control levels by 240 min. Plasma corticosterone concentrations reached a peak (6.7-fold greater than basal levels) at 30 min. Orexin-A at a higher dose (30 microg/rat) also produced a rapid increase in plasma ACTH and corticosterone concentrations. The area under the curve for plasma levels of ACTH was similar for both doses of orexin-A. In a second study, orexin-A (10 microg/rat) was injected i.c.v. and brains and pituitaries were rapidly removed after 240 min. In situ hybridization histochemistry revealed that CRF and AVP mRNA levels were significantly increased in the parvocellular cells of the PVN. Pro-opiomelanocortin mRNA levels in the pituitary gland were not significantly elevated in response to orexin-A. These results suggest that orexin-A is able to act centrally to activate the hypothalamic-pituitary-adrenal axis involving stimulation of both CRF and AVP expression.
Asunto(s)
Arginina Vasopresina/metabolismo , Proteínas Portadoras/farmacología , Hormona Liberadora de Corticotropina/metabolismo , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Péptidos y Proteínas de Señalización Intracelular , Neuronas/metabolismo , Neuropéptidos/farmacología , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Hormona Adrenocorticotrópica/sangre , Animales , Arginina Vasopresina/genética , Estado de Conciencia , Corticosterona/sangre , Hormona Liberadora de Corticotropina/genética , Expresión Génica/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/citología , Sistema Hipotálamo-Hipofisario/metabolismo , Hibridación in Situ , Inyecciones Intraventriculares , Masculino , Neuronas/efectos de los fármacos , Orexinas , Sistema Hipófiso-Suprarrenal/citología , Sistema Hipófiso-Suprarrenal/metabolismo , ARN Mensajero/análisis , Ratas , Ratas Sprague-DawleyRESUMEN
AIM: To clarify whether centrally delivered leptin can access the circulation and to determine to what extent the effects of i.c.v. h-leptin and m-leptin on body weight and plasma corticosterone are due to reduced food intake. METHODS: Male lean Zucker rats were infused i.c.v. with recombinant m-leptin or h-leptin (42 microg/day) for 7 days. Terminal plasma leptin levels were measured using selective r-leptin, m-leptin and h-leptin RIA. Plasma h-leptin and corticosterone levels were determined on days 0, 2, 4 and 6 of h-leptin infusion. Interscapular brown adipose tissue weight and UCP-1 mRNA expression (an indicator of thermogenic capacity) were also measured. RESULTS: The terminal plasma leptin level was elevated (from 2.2 +/- 0.4 to 42.7 +/- 20.2 ng/ml) in the h-leptin-treated lean rats to levels similar to those in vehicle i.c.v. infused fa/fa rats (72.2 +/- 4.7 ng/ml), but this was only detectable when the h-leptin radioimmunoabsorbent assay (RIA) was used. Further, both m-leptin and h-leptin infusions in lean rats elevated terminal plasma corticosterone (352 +/- 37 and 389 +/- 55 ng/ml, respectively) to levels similar to those in i.c.v. rats (386 +/- 62 ng/ml), whereas diet-restriction by pair-feeding, with the h-leptin group, in lean rats had no effect (207 +/- 45 ng/ml). The increase in plasma corticosterone level coincided with the maximum hypophagic effects of leptin and preceded the appearance and sustained elevation of exogenous human leptin in the circulation. Both m-leptin and h-leptin i.c.v. infusion reduced body weight gain (3% and 4%, respectively, compared to pair-fed group) and increased UCP-1 expression (11-fold and 16-fold, respectively) in lean rats. However, h-leptin elicited an earlier effect than m-leptin on body weight, manifested as an earlier reduction in food intake and greater increase in UCP-1 expression. h-Leptin also elicited a greater reduction in body weight gain than did pair-feeding. CONCLUSIONS: Intracerebroventricular-infused m-leptin or h-leptin was detected in the circulation. Furthermore, m-leptin and h-leptin elevated plasma corticosterone levels and h-leptin caused some weight loss in lean rats independently of its suppression of food intake. The elevation of corticosterone levels in the lean rats may be a mechanism whereby they resist excessive weight loss in response to leptin.
Asunto(s)
Corticosterona/sangre , Metabolismo Energético/efectos de los fármacos , Leptina/farmacología , Tejido Adiposo Pardo/efectos de los fármacos , Tejido Adiposo Pardo/metabolismo , Animales , Encéfalo/metabolismo , Proteínas Portadoras/genética , Epidídimo , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Infusiones Intravenosas , Canales Iónicos , Leptina/administración & dosificación , Leptina/sangre , Masculino , Proteínas de la Membrana/genética , Ratones , Mitocondrias/metabolismo , Proteínas Mitocondriales , Obesidad/sangre , Obesidad/genética , Obesidad/metabolismo , ARN Mensajero/genética , Ratas , Ratas Zucker , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/farmacología , Delgadez , Factores de Tiempo , Transcripción Genética/efectos de los fármacos , Proteína Desacopladora 1Asunto(s)
Peso Corporal , Corticosterona/sangre , Leptina/administración & dosificación , Tejido Adiposo/anatomía & histología , Tejido Adiposo Pardo/metabolismo , Animales , Regulación de la Temperatura Corporal , Peso Corporal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Proteínas Portadoras/genética , Ingestión de Alimentos/efectos de los fármacos , Humanos , Canales Iónicos , Masculino , Proteínas de la Membrana/genética , Ratones , Proteínas Mitocondriales , Obesidad/fisiopatología , Tamaño de los Órganos/efectos de los fármacos , ARN Mensajero/análisis , Ratas , Ratas Zucker , Proteína Desacopladora 1RESUMEN
OBJECTIVE: To investigate whether chronic administration of the long-acting glucagon-like peptide-1 receptor agonist exendin-4 can elicit sustained reductions in food intake and body weight and whether its actions require an intact leptin system. RESEARCH METHODS AND PROCEDURES: Male lean and obese Zucker (fa/fa) rats were infused intracerebroventricularly with exendin-4 using osmotic minipumps for 8 days. RESULTS: Exendin-4 reduced body weight in both lean and obese Zucker rats, maximum suppression being reached on Day 5 in obese (8%) and Day 7 in lean (16%) rats. However, epididymal white adipose tissue weight was not reduced, and only in lean rats was there a reduction in plasma leptin concentration. Food intake was maximally suppressed (by 81%) on Day 3 in obese rats but was reduced by only 18% on Day 8. Similarly, in lean rats food intake was maximally reduced (by 93%) on Day 4 of treatment and by 45% on Day 8. Brown adipose tissue temperature was reduced from Days 2 to 4. Plasma corticosterone was elevated by 76% in lean but by only 28% in obese rats. DISCUSSION: Chronic exendin-4 treatment reduced body weight in both obese and lean Zucker rats by reducing food intake: metabolic rate was apparently suppressed. These effects did not require an intact leptin system. Neither does the absence of an intact leptin system sensitize animals to exendin-4. Partial tolerance to the anorectic effect of exendin-4 in lean rats may have been due to elevated plasma corticosterone and depressed plasma leptin levels, but other counter-regulatory mechanisms seem to play a role in obese Zucker rats.
Asunto(s)
Peso Corporal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Leptina/metabolismo , Obesidad/fisiopatología , Péptidos/administración & dosificación , Receptores de Glucagón/agonistas , Ponzoñas , Tejido Adiposo/anatomía & histología , Tejido Adiposo Pardo/fisiopatología , Animales , Temperatura Corporal , Corticosterona/sangre , Ingestión de Alimentos/efectos de los fármacos , Epidídimo , Exenatida , Receptor del Péptido 1 Similar al Glucagón , Masculino , Tamaño de los Órganos , Péptidos/farmacología , Ratas , Ratas ZuckerRESUMEN
Rosiglitazone (BRL 49653), a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist and potent insulin action-enhancing agent, was given in the diet (50 micromol/kg of diet) to male Zucker rats ages 6-7 weeks for 9 months (prevention group). In this treatment mode, rosiglitazone prolonged the time to onset of proteinuria from 3 to 6 months and markedly reduced the rate of its subsequent progression. Progression was also retarded when treatment was commenced (intervention group) after proteinuria had become established (4 months; ages 24-25 weeks). In either treatment mode, rosiglitazone normalized urinary N-acetyl-beta-D-glucosaminidase activity, a marker for renal proximal tubular damage, and ameliorated the rise in systolic blood pressure that occurred coincidentally with the development of proteinuria in Zucker fatty control rats. The renal protective action of rosiglitazone was verified morphologically. Thus in the prevention group there was an absence of the various indexes of chronic nephropathy that were prominent in the Zucker fatty control group, namely, glomerulosclerosis, dilated tubules containing proteinaceous casts, a loss of functional microvilli on the tubular epithelium, and varying degrees of chronic interstitial nephritis. An intermediate pathology was observed in the intervention group. Also, pancreatic islet hyperplasia, ultrastructural evidence of beta-cell work hypertrophy, and derangement of alpha-cell distribution within the islet were prominent features of Zucker fatty control rats, but these adaptive changes were ameliorated (intervention group) or prevented (prevention group) by rosiglitazone treatment. These data demonstrate that treatment of Zucker fatty rats with rosiglitazone produced substantial protection over a prolonged period against the development and progression of renal injury and the adaptive changes to pancreatic islet morphology caused by sustained hyperinsulinemia.
Asunto(s)
Hipoglucemiantes/uso terapéutico , Islotes Pancreáticos/efectos de los fármacos , Enfermedades Renales/prevención & control , Obesidad/tratamiento farmacológico , Enfermedades Pancreáticas/prevención & control , Ratas Zucker/fisiología , Tiazoles/uso terapéutico , Tiazolidinedionas , Acetilglucosaminidasa/orina , Albuminuria , Animales , Presión Sanguínea/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Histocitoquímica , Inmunohistoquímica , Riñón/metabolismo , Riñón/patología , Masculino , Obesidad/metabolismo , Obesidad/patología , Páncreas/patología , Proteinuria/orina , Ratas , Rosiglitazona , SístoleRESUMEN
Indices of carbohydrate and lipid metabolism were investigated in male New Zealand genetically hypertensive and normotensive rats. Cross-breeding of male rats of these strains with female Brattleboro diabetes insipidus rats also provided the opportunity to examine the metabolic impact of vasopressin and its deficiency in hypertensive and normotensive rats. Hypertensive and normotensive rats, with or without diabetes insipidus, were fasted for 24 h, exsanguinated and their blood/plasma analysed for various indices of carbohydrate and lipid metabolism. Whilst each group of rats maintained fasted normoglycemia, hypertensive rats, with or without vasopressin-deficiency, were hypoinsulinaemic relative to normotensive counterparts. Moreover, hypertensive or normotensive vasopressin-deficient rats were hypoinsulinaemic relative to vasopressin-replete counterparts. In vasopressin-replete rats, the apparently improved insulin sensitivity in hypertension was associated with significant falls in plasma glucagon, triglycerides and total cholesterol. Finally, normotensive vasopressin-deficient rats were hypoglucagonaemic relative to the vasopressin-replete group. These data demonstrate that independent of vasopressin status, hypertension in the New Zealand strain and the diabetes insipidus hybrid was associated with improved insulin sensitivity. However, endogenous vasopressin exercises an influential role in carbohydrate and lipid metabolism in normotensive rats.
Asunto(s)
Glucemia/metabolismo , Glucagón/sangre , Hipertensión/sangre , Lípidos/sangre , Vasopresinas/deficiencia , Animales , Colesterol/sangre , Cruzamientos Genéticos , Diabetes Insípida/sangre , Diabetes Insípida/complicaciones , Femenino , Hipertensión/complicaciones , Insulina/sangre , Masculino , Ratas , Ratas Brattleboro , Triglicéridos/sangreRESUMEN
The obese Zucker rat (OZR) exhibits a missense mutation in the cDNA for the leptin receptor, producing a single amino acid substitution in the extracellular domain of the receptor. A mutation in the leptin receptor gene of the db/db mouse prevents the synthesis of the long splice variant of the receptor. The possibility that the OZR, like the db/db mouse, is refractory to the actions of murine leptin was tested by infusing the protein intracerebroventricularly via a minipump for 7 days. Lean Zucker rats (LZR) infused with leptin acted as positive controls, and other groups of OZR and LZR were infused with vehicle. In LZR, leptin reduced bodyweight and food intake and increased brown adipose tissue (BAT) temperature. Plasma corticosterone increased (61%) in these rats, and plasma triglycerides fell (78%). Leptin treatment improved tolerance to an oral glucose load (16% reduction in the area under the blood glucose curve) while lowering plasma insulin. In OZR, the actions of leptin were blunted. Food intake was slightly, but not significantly, reduced. Although there was a reduction in the rate of increase in body mass, the effect of leptin was about half that seen in LZR. BAT temperature and glucose tolerance were unchanged. In contrast to the elevated plasma corticosterone seen in LZR, leptin reduced the level of this hormone (27%) in OZR. In OZR and LZR treated with leptin, the plasma leptin levels were increased 24-fold and 47-fold, respectively. The results suggest that leptin retains some efficacy in OZR, although these rats are less responsive than LZR.
Asunto(s)
Encéfalo/efectos de los fármacos , Obesidad/fisiopatología , Proteínas/farmacología , Tejido Adiposo Pardo/efectos de los fármacos , Tejido Adiposo Pardo/fisiopatología , Animales , Glucemia/metabolismo , Temperatura Corporal , Peso Corporal/efectos de los fármacos , Corticosterona/sangre , Ingestión de Alimentos/efectos de los fármacos , Metabolismo Energético , Bombas de Infusión Implantables , Insulina/sangre , Leptina , Masculino , Ratones , Proteínas/administración & dosificación , Proteínas/metabolismo , Ratas , Ratas Zucker , Proteínas Recombinantes/farmacología , Triglicéridos/sangreAsunto(s)
Conducta Alimentaria , Neuropéptido Y/farmacología , Receptores de Neuropéptido Y/fisiología , Animales , Apetito , Línea Celular , Relación Dosis-Respuesta a Droga , Humanos , Cinética , Masculino , Neuropéptido Y/análogos & derivados , Fragmentos de Péptidos/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
In the absence of the potentially confounding influence of vasopressin in hypertension, the effects of atrial natriuretic peptide (ANP) on arterial blood pressure and renal handling of water and sodium were assessed from comparison of responses to intravenous ANP infusion in anaesthetized vasopressin-deficient New Zealand genetically hypertensive (DI/H) rats and their normotensive substrain (DI/N). After 320 min of hypotonic saline infusion, plasma ANP concentration was significantly higher in DI/H compared with DI/N rats. ANP administration increased circulating ANP concentration in both groups. Plasma angiotensin II concentration was higher in DI/H than in DI/N rats; infusion of ANP raised circulating angiotensin II in both groups though this achieved statistical significance only in DI/N rats. Plasma aldosterone concentrations were initially similar in normotensive and hypertensive animals and, in both, were reduced markedly by I.V. ANP infusion. Administration of ANP produced sustained hypotension in both groups. However, the hypotensive effect of ANP was more pronounced in DI/H compared with DI/N rats. Heart rate was initially similar in the two groups, and infusion of ANP produced no detectable change. By comparison with animals maintained on hormone-free infusate, urine flow increased markedly over the 80 min period of ANP infusion in both groups, by 142% in DI/H rats and 127% in DI/N rats. ANP administration produced a natriuresis in both groups but the increase in Na+ excretion was much greater in DI/H (342%) than in DI/N (139%) rats. It appears from the current study that vasopressin-deficient hypertensive rats are more sensitive to ANP with regard to effects on blood pressure and renal excretion than their vasopressin-deficient normotensive substrain. These differences may, in part, reflect adjustments to long-term elevation in blood pressure and in plasma ANP concentration in hypertension and, in part, rely on the associated disturbances in related endocrine systems.
Asunto(s)
Factor Natriurético Atrial/fisiología , Hipertensión/fisiopatología , Ratas Endogámicas/fisiología , Vasopresinas/deficiencia , Aldosterona/sangre , Angiotensina II/sangre , Animales , Factor Natriurético Atrial/sangre , Presión Sanguínea , Modelos Animales de Enfermedad , Glándulas Endocrinas/fisiopatología , Frecuencia Cardíaca , Hipertensión/genética , Riñón/fisiopatología , Masculino , Ratas , Sodio/orina , Agua/metabolismoRESUMEN
1. The interaction between atrial natriuretic factor (ANF) and angiotensin II (Ang II) within the brain to influence renal function and blood pressure was studied in Inactin-anaesthetized male Sprague-Dawley rats. 2. Central infusion of ANF produced a diuresis which was associated with a significant decrease in plasma arginine vasopressin (AVP) level. There was no change in sodium excretion rate over the 80 min of intracerebroventricular ANF infusion and ANF produced no detectable change in mean arterial blood pressure. 3. Central Ang II administration produced a significant decrease in urine flow, which was associated with elevated plasma AVP, an increase in sodium excretion and a rise in mean arterial blood pressure. 4. Combined ANF and Ang II infusion produced an antidiuresis, which was associated with increased plasma AVP concentration. Both the natriuretic and vasopressor actions of central Ang II were abolished when ANF was co-administered. 5. It is concluded that ANF and Ang II interact centrally; ANF antagonizes the pressor and natriuretic effects but not the antidiuretic effects of central Ang II. These data suggest the possibility of distinct and separate sites within the brain through which Ang II influences vasopressin release and renal sodium handling and elevates blood pressure.